The invention relates to a process for the production of extract-containing pharmaceutical formulations such as tablets, film-coated tablets, sugar-coated tablets inter alia.
Plant-based medicinal products contain in solid preparations dry extracts from herbal drugs which are generally produced by extraction with alcohol/water mixtures and subsequent evaporation and drying. The dosage of these extracts in each single dose may vary within wide limits. The extracts are hygroscopic and are difficult to compress into pharmaceutical formulations such as tablets or cores for coated tablets. The extracts normally contain mucilages which impede subsequent disintegration of the tablets, film-coated tablets or sugar-coated tablets.
In the state of the art, pharmaceutical formulations such as tablets or tablet cores for film-coated tablets and sugar-coated tablets are produced by direct tableting or previous granulation of the active ingredients and, where appropriate, excipients. Direct tableting is a simple process because the ingredients are merely mixed and compressed into tablets. This results in no exposure to moisture during the granulation, and hydrolysis processes are avoided. Likewise, temperature stress during drying of the granules is precluded.
However, direct tableting frequently fails with many extracts because of the poor flow characteristics and the poor compressibility of the extracts. To granulate the active ingredients, they are mixed with solvents or binder solutions and granulated in known devices and then dried.
Granulation by moistening with solvents or the use of binder solutions entails an increase in the particle size and standardization of the particle size distribution of the medicinal substances. At the same time, the flow characteristics of the granules are improved by comparison with the starting substances. It is likewise possible to achieve a greater accuracy of dosage in the tableting machine.
Aqueous granulation can be used only rarely for extract-containing products because extracts are prone, because of their high solubility and high hydrophilicity, to jamming or clogging very quickly during the granulation process.
Using organic solvents for granulation is at present difficult for toxicological and environmental reasons.
EP A 0 530 833 discloses a process for producing Kampo extract-containing hard gelantin capsules. This entails the Kampo extract being compressed in a first stage together with amounts between 0.5 and 1% by WEIGHT of magnesium stearate and other conventional excipients, and crushed and classified. The resulting granules are mixed with a further amount of magnesium stearate and packed into hard gelatin capsules. Addition of magnesium stearate to the granulated extract which has already been prepared that is to say, addition of magnesium stearate in the outer phase, is obligatory. This publication specifies that the addition of the magnesium stearate takes place not as a lubricant, but to improve the dissolving properties of the pharmaceutical hard gelatin capsules.
The invention is based on the object of preparing extracts so that they can be satisfactorily incorporated in an amount of from 100 to 1000 mg of extract per single dose into pharmaceutical formulations such as tablets, film-coated tablets, sugar-coated tablets and the like, and are released from the pharmaceutical formulations within an appropriate time.
In the process according to the invention, the extract powders are compacted together with a lubricant. For this purpose, the extract powder is mixed with amounts of from 0.5 to 10% by weight of lubricants and is compacted. Amounts of 2-5% by weight of lubricants are preferably used in the compaction. Particularly suitable amounts of lubricant are 3% by weight.
The compaction takes place in devices suitable for this purpose. Thus, it is possible to compress the mixture to flakes between two rolls in a compactor. A pressure of from 20 to 120 kN is used for producing the compacts in the compactor. Preferred pressures are from 35 to 65 kN. Particularly suitable pressures are from 42 to 48 kN. With an effective width of the roll of 5 cm the resulting specific pressure is from 4 to 25 kN/cm.
To improve the compression, the device for the actual compaction can be preceded by a precompaction device. It is possible in this way, on use of a compactor, to employ one preceded by a precompaction screw. The precompaction screw is connected to the compactor and operates with the screw revolving at 20 to 60 revolutions/min. Preferred values for the number of revolutions are from 25 to 35 revolutions/min. The resulting flakes are then reduced in size while dried to granules of defined particle size. The reduction in size and granulation preferably take place in a screening machine.
The resulting granules are compressed to pharmaceutical formulations after addition of excipients such as dry binders, disintegrants and, where appropriate, flow regulators. The compaction of the extract with a lubricant means that no further lubricant is required in the outer phase. Addition of a flow regulator that increases capillary forces in the outer phase affords pharmaceutical formulations which have a shorter disintegration time and greater hardness compared with friability of the resulting pharmaceutical formulations.